Project Summary Addiction is destructive for addicted individuals and, simultaneously, has devastating societal consequences. An important goal of addiction research is to understand the neurobiological mechanisms underlying this disease state. Evidence suggests that chronic psychostimulant use alters hippocampal function which may lead to emotional states that promote the cycle of addiction. The hippocampus is functionally segregated along its longitudinal axis into dorsal and ventral regions where the ventral region preferentially regulates stress and anxiety, while the dorsal preferentially regulates spatial learning and memory. The proposed studies will increase understanding of the mechanisms through which cocaine modulates hippocampal function to influence behavior. Hilar mossy cells are an under-investigated component of the local circuitry of the hippocampal formation. The glutamatergic mossy cell innervates both excitatory granule cells and inhibitory interneurons, therefore, a proposed major function of mossy cells is to integrate the functions of large numbers of neurons along the septotemporal axis of the hippocampus. Glycogen synthase kinase-3? (GSK3?) is a highly conserved serine/threonine protein kinase involved in hippocampus-regulated behaviors. Accordingly, the activation of hilar mossy cells and mossy cell GSK3? pathway activity by re-exposure to a cocaine-paired environment will be characterized in the dorsal and ventral hippocampus (Aim 1). Next, the role of dopamine D2 receptors and GSK3? activation by cocaine in the development and expression of cocaine-associated conditioned place preference behavior will be investigated (Aim 2). The results of the proposed studies will demonstrate the impact of cocaine exposure on the local hippocampal circuitry and the cellular pathways involved in cocaine reward-context associations. These studies will lay the groundwork for more comprehensive studies investigating the influence of psychostimulants on the hippocampal circuitry and provide critical insight into the contribution of mossy cells to the mechanisms through which cocaine alters hippocampal function and plasticity implicated in addiction-related behaviors. Reversing or preventing drug- induced adaptations to the hippocampus may prove beneficial in the treatment of the complex process of addiction.